HU194050B - Process for loading of swelling, not poluable in water polimers with medroxi-progresteron acetat - Google Patents

Abstract

A water-swellable, water-insoluble polymer is loaded with methylhydroxyprogesterone acetate (MAP) by: (a) preparing and grinding a mixture of a said polymer and MAP; or (b)(i) preparing a mixture of a said polymer which is stable under the heating to which the mixture is subjected in step (ii) and MAP and (ii) heating the mixture up to the melting temperature of MAP; or (c) swelling a said polymer with a MAP solution capable thereof and drying the resulting swollen polymer/MAP system. The MAP loaded polymer is useful as a pharmaceutical composition.

Description

The present invention relates to a process for the incorporation of 6α-methyl-17α-hydroxy-progestione acetate (medroxyproproesterester acetate or MAP) into water-swellable, water-insoluble polymers for the preparation of pharmaceutical compositions.

MAP was produced independently in 1958 by two research teams. MAP is a synthetic steroid derived from progesterone and exhibits progestin activity upon oral or intramuscular administration.

MAP is also used in tumor therapy at higher doses, orally or intramuscularly. However, very high doses should be used for the above therapeutic purposes when administered orally as the bioavailability of the active ingredient is very poor. The above property is related to poor wetting and dissolution of the active ingredient in water or biological media, and the absorption of the active ingredient is directly determined and limited by the above characteristics.

The wettability and dissolution properties of the active ingredient greatly affect its bioavailability. There are many cases in which a highly active drug exhibits poor absorption due to its poor solubility properties. To overcome the above difficulties, particle size is usually reduced or wetting agents are added to the active ingredient, but often the above measures will not produce satisfactory results. Therefore, new formulation methods and novel formulations are being developed to provide better absorption. Two new lines of research are now known to solve the problem, one based on the production of solid dispersions and the other based on the inclusion of inclusion compounds.

In the above approach, the active ingredient is molecularly dispersed in the carrier, which is usually a water-soluble polymer [S. Riegelman, W.L. Chiou, 987 588 4/1976, Canada], according to which the active ingredient is converted into molecular complexes by water-soluble cyclodextrins [J. Proceedings: Cyclodextrins and their Exclusion Compounds Academic Publisher Budapest, 1982],

According to the process of the present invention, MAP is added to a water-swellable, water-insoluble polymer or polymer such as crosslinked polyvinylpyrrolidone (hereinafter referred to as crosslinked PVP (National Formulary XV, Supplement 3, 368.0.)), Sodium carboxylic acid. -methylcellulose [National Formulary XV, Supplement 3, 367.0.], cross-linked dextran, etc. - or a mixture thereof, using three different methods.

In the form thus obtained, where the MAP is in a water-swellable, water-insoluble polymer or polymer, the dissolution and wetting properties of MAP are greatly improved in aqueous or biological media due to the following factor or factors:

1. The dissolution energy of MAP is reduced due to complete or partial amorphization of the MAP or conversion of its original crystalline state to a higher energy state (lower melting point);

2. The molecules of MAP are dispersed in the network or network of the highly hydrophilic and swellable polymer, thereby increasing the wettability of MAP.

According to the invention, methylhydroxy-progesterone acetate (MAP) is incorporated into a water-swellable, water-insoluble polymer by: a) grinding a mixture of the polymer and MAP; obsession

b) (1) preparing a mixture of polymer stable at the melting point of MAP and MAP and (II) heating the mixture to a temperature corresponding to the melting point of MAP; obsession

c) swelling the polymer with a solution of MAP and drying the resulting swollen polymer MAP system. The basic advantage of hydrophilic, swellable, water-insoluble polymeric drug delivery systems over solid dispersions and inclusion compounds is that

1. the high wettability and hydrophilicity of the hydrophilic, swellable, water-insoluble polymers will result in a higher wettability of the active ingredient;

2. the system disintegrates more rapidly in water and the drug particles disperse faster (some of the hydrophilic, swellable, water-insoluble polymers useful in the process of the present invention are actually used as disintegrants for oral solid dosage forms);

3. avoiding the formation of a viscous layer * around the active ingredient, which occurs when water-soluble polymers are used and inhibits diffusion of the active ingredient and slows down the dissolution process.

The systems of the present invention, comprising MAP and one or more hydrophilic, swellable, water insoluble polymers such as crosslinked PVP, crosslinked sodium carboxymethylcellulose, crosslinked starch, crosslinked dextran, and the like. they are - a common feature that

1. they have high swelling properties (0.1-100 mL water uptake per 1 g dry polymer), swell and disintegrate well in water and biological fluids as a result of their high dispersibility and immediate release of MAP molecules;

2. high swelling rate in water (for example, crosslinked PVP achieves maximum swelling within 5 minutes), due to the above-mentioned properties, the swelling, disintegration, dispersion and dissolution of the MAP molecules occur in a very short time;

3. insoluble in water, this property eliminates unwanted effects that can slow down the dissolution of MAP (e.g., the formation of a viscous layer around MAP) and promotes the formation of a finely dispersed homogeneous suspension that ensures rapid absorption from the stomach.

The above systems of MAP and water insoluble swellable polymer can be prepared in three ways:

1. grinding the mixture of MAP and polymer;

2. heating the mixture of MAP and polymer to a temperature of the melting point of MAP;

3. swelling the polymer with a solution of MAP and drying.

These three methods are described in detail below.

1. Grinding of MAP and Polymer

A dry mixture of MAP and one or more of the above-mentioned swellable, water-insoluble polymers is placed in a rotary ball mill, vibration ball mill, auto-abrasive mill or other suitable grinding apparatus and comminuted until crystalline MAP is completely amorphized. The completion of the amorphization may be verified by the lack of an endothermic peak of the solid-liquid transition characteristic of the crystalline M AP (i.e., the melting enthalpy is practically 0) in the differential scanning calorimetrically recorded thermogram of the drug-polymer system obtained. Grinding of the mixture of MAP and the swellable polymer can be completed at any amorphization degree of MAP between 0 and 100% (as measured by a decrease in the melting enthalpy of the crystalline MAP), even if the MAP crystalline polymer may be milled differently, to a higher energy level. The above transformation is indicated by the shift of the original endothermic peak towards lower temperatures. The new MAP at higher energy levels has higher dissolution rates and improved bioavailability.

The weight ratio of MAP to swellable water-insoluble polymer in the mixture to be milled can vary from 1 0.1 to 1: 100, preferably from 1: 1 to 1: 100. For each batch, the milling time required to achieve the desired degree of amorphization or higher energy level should be controlled, so that the most appropriate weight ratio and milling time for each MAP polymer system should be limited. The weight ratios of the active ingredient: swellable water insoluble polymer and grinding times are described below.

The ground mixture of MAP and swellable polymer thus obtained can then be sieved to remove any aggregates and then further blended in a mixer for further homogenization.

The resultant powdered mixture can then, if desired, be added to solid dosage forms such as capsules, tablets, etc., after the addition of customary pharmaceutical additives. - can be used to produce.

2, Heating the mixture of MAP and polymer to a temperature corresponding to the melting point of MAP

Dry the dry mixture of the crystalline MAP and the swellable, water-insoluble polymer, which exhibits good thermal stability at the temperature corresponding to the melting point of the MAP, in a suitable vessel in a high-vacuum, high vacuum oven; after aspiration of air, nitrogen is passed over the MAP polymer mixture and the temperature is raised to a value sufficient to ensure melting of the MAP. Alternatively, the mixture of MAP and polymer may be placed in a glass flask of a rotary evaporator and air aspirated under nitrogen over the MAP polymer mixture and heated to a temperature sufficient to melt the MAP in an oil bath. Other heat transfer equipment, such as a hot plate, case oven, tube furnace, etc. can also be used if the temperature can be properly controlled and kept constant.

The MAP polymer mixture is heated until the desired degree of amorphization (0-100%) is achieved, and the degree of amorphization can be measured by differential scanning calorimetry,

The weight ratio of MAP to polymer in the mixture to be heated may range from 1.0.1 to 1: 100, preferably from 1: 1 to 1: 100 MAP polymer. The heating time required to achieve the desired degree of amorphization must be determined for each MAP polymer mixture and for each mixture. The weight ratio, temperature and heating time of the components in the MAP polymer mixtures are given below.

The heat-treated mixture of MAP and the swellable polymer can then be sieved to remove any aggregates and subsequently mixed in a mixer for further homogenization. The resulting powdered MAP polymer blend may optionally be formulated with various solid dosage forms such as tablets, capsules, and the like after the addition of customary pharmaceutical excipients. - can be used to produce.

3, Swelling the polymer with MAP solution and drying

MAP can be dissolved in any conventional solvent, such as methylene chloride, Woroform, acetone, etc., at the desired concentration. The resulting solution is then poured into a predetermined amount of water-insoluble swellable polymer or mixture of polymers and the resulting swollen powder is then dried in a suitable apparatus. The amount of MAP solution that can be poured onto a predetermined amount of polymer can be any amount up to the maximum swelling of the polymer in a given solvent. The swelling operation may be carried out in any suitable apparatus. For example, a predetermined amount of MAP solution is applied to the desired amount of swellable water-insoluble polymer placed in a flask, thoroughly mixed, and the resulting swollen powder dried in a vacuum oven. Alternatively, place the desired amount of swellable, water-insoluble polymer in a glass flask of a rotary evaporator, add the weighed amount of MAP solution, and heat the resulting swollen polymer to dryness.

The swelling! The weight ratio of MAP polymer in the MAP polymer mixture obtainable by the process of the invention may range from 1: 0.1 to 1: 100, preferably from 1: 1 to 1: 100. The amount of MAP that can be added to the polymer in each solvent-polymer system is determined by the solubility of the MAP in the particular solvent and the swelling volume of the polymer in the particular solvent. For each solvent-polymer system, varying the amount of MAP added to the polymer can result in a depreciation of 0-100%, which is sufficient to significantly increase the dissolution rate of the MAP, or convert the MAV to a higher energy level. Examples of weight ratio of MAP polymer, volume of MAP solution and weight of polymer are given below.

The MAP polymer mixture produced by the swelling-drying process may be screened to remove any aggregates and then mixed in a suitable apparatus for further homogenization. The resulting powdered MAP polymer blend may optionally be formulated with any desired solid dosage forms, e.g. - can be used to produce.

The dosage to be administered from the MAP polymeric system produced by the method of the invention will be influenced by many factors, such as the age, condition, and symptoms of the subject being treated.

The following examples illustrate the invention.

mix in a beater, place in an automatic rubbing mill and grind for 3 hours. The resulting MAP-crosslinked PVP mixture was sieved through a 260 µm screen and then mixed in a mixing apparatus.

194.050 lyc. The powdered MAP crosslinked PVP mixture may be used to prepare any desired solid dosage form.

Example 2

The MAP crosslinked PVP mixture prepared according to Example 1 is prepared as follows: MAP Crosslinked Masterbatch 200 mg Crosslinked PVP 40 mg (Pure crosslinked PVP is added as a disintegrant).

The above ingredients are thoroughly mixed in a suitable apparatus and then compressed into tablets using a 13 mm flat die.

Example 3

The MAP-crosslinked PVP mixture prepared according to Example 1 was formulated into capsules having the following composition: MAP-crosslinked PVP base system 200.0 mg of crosslinked PVP 40.0 mg of magnesium stearate 2.5 mg

Example 4

0.7 g of crystalline MAP and 3.5 g of cross-linked sodium carboxymethyl cellulose are mixed in a suitable apparatus, then placed in an automatic rubbing mill and ground for 3 hours. The resulting MAP-crosslinked sodium carboxymethylcellulose powder is then sieved through a 260 µm sieve and blended in a suitable mixer. The powdered MAP-crosslinked sodium carboxymethylcellulose system can be used to make any solid dosage form.

, Example 5

0.2 g of crystalline MAP and 1.0 g of crosslinked PVP are mixed in a suitable apparatus, then placed in a rotary evaporator glass flask and heated in an oil bath at 215 ° C for 45 minutes under a stream of nitrogen. The resulting MAP-crosslinked PVP system is then sieved through a sieve having a mesh size of 260 µm and mixed in a suitable mixer. The resulting powdered mixture can then be used to form any desired solid dosage form.

Example 6

The MAP-crosslinked PVP mixture prepared in Example T is prepared as a tablet having the following composition: MAP-crosslinked PVP heat treated mixture 300 mg crosslinked PVP 60 mg (Pure crosslinked PVP is added as a disintegrant).

The above components are thoroughly mixed in a suitable machine and then a 13 mm sheet is pressed into a tablet press.

Example 7 Crystalline MAP g is dissolved in 100 ml of methylene chloride. 20 ml of the above solution were poured into 5 g of crosslinked PVP with gentle stirring in a mortar. The resulting expanded MAP crosslinked PVP mixture was then dried in a vacuum oven at 60 ° C for 2 hours. The resulting dry powder was sieved through a sieve having a mesh size of 260 fxn and mixed in a suitable apparatus. The powdered mixture may be used to form any desired solid dosage form.

Example 8

The MAP-crosslinked PVP mixture prepared according to Example 7 was manufactured using a 13mm flat-die tableting machine to form the following compositions: MAP-crosslinked PVP (swelling system) 300 mg

Example 9

The MAP-crosslinked PVP blend prepared according to Example 7 gave tablets of the following composition: MAP-crosslinked PVP (swelling system) 600 mg microcrystalline cellulose PH-101 150 mg manganese stearate 6 mg

Characteristics of MAP swelling polymer system in vitro

Differential scanning calorimetry data

In FIG. and Examples 4, the MAP polymer system produced by grinding is differential calorimetric. (D.S.C.) (T.A. 3000, Mettler) is given in Table I. ______ _____

Comparing the above data with that of pure MAP and micronized pure MAP, we find that the original melting temperature of the 13 weighted MAP crosslinked PVP blend is reduced by 60% after 3 hours grinding to a lower melting point of 205.6 ° C). shifts (196 ° C). The 1: 5 weight ratio MAP crosslinked sodium carboxymethylcellulose has a 50% damping rate after 3 hours of grinding.

In Example 5, the differential calorimetric data for the MAP swellable polymer system produced by heat treatment is also shown in Table I, where the MAP depression is almost complete.

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Table 1: Differential calorimetric data for M AP swelling polymer systems

MAP preparation melting point CC) melting Heat (J / g) t Melting heat relative to original (%) Pure crystalline MAP 205-206 88.003 100.0 Micronized pure MAP (3 hour grinding) 205.3 82.798 94.1 MAP Crosslinked PVP 13 Ratio System (Grinding Method). example 195.9 33.100 37.7 MAP Crosslinked Sodium Carboxymethyl Cellulose 1: 5 System (Grinding Method) Example 4 204.4 44.600 50.6 MAP Crosslinked PVP 1 3 Ratio System (Heat Treatment Method) Example 5 - 0 ~ 0 ~ MAP Crosslinked PVP 1: 5 System (Swelling Method) Example 7 195.2 85.4 97.1

In Example 7, the MAP polymer system produced by swelling with MAP solution showed no decrease in melting temperature, but a decrease in the original melting point was observed.

2, Solubility data

The solubility (saturation concentration) of the MAP swellable polymer system was determined by placing an excess of the powdered system corresponding to 50 mg MAP in 50 ml flasks containing pH 5.5 buffer at 37 ° C, placed on a shaking thermostat, aliquots of the solution were taken, the samples filtered through a Millipore membrane filter, and the concentration of MAP in the filtrate after dilution with methanol was determined by spectrophotometry (SP

-100, Pye Unicam), and was also determined by HPLC (column: Sphrisorb S30DS2; mobile phase: acetonitrile / water 7030; flow rate: 1 mL / min; OV detection, λ = 242 nm), diluted with acetonitrile. .

Like II. In the very short time ⁰ shown in the Table, significant solubility increase can be achieved for MAP in the MAP-dense polymer system produced by all three processes. Of particular interest is the observation that MAP concentrations obtained by dissolving polymeric systems are 10 to 100 times higher than those obtained by dissolving crystalline MAP at a dissolution time of 5 minutes.

II. Solubility of MAP-swelling polymer systems in phosphate buffer solution (pH 5.5) at 37 ° C

MAP preparation 5 minutes Solubility (mcg / ml) Dissolution time 6 hours 15 minutes 1 hour Pure crystalline MAP 0.04 0.32 0.68 1.00 MAP Crosslinked PVP 1: 3 System (Grinding Method) Example 1 2.26 3.08 2.90, 5.28 MAP Crosslinked PVP 1: 5 System (Heat Treatment Method) Example 5 3.83 6.10 4.76 3.28 MAP Networked PVP 1: 5 System (Swelling Method) Example 7 1.00 1.61 1.69 2.04

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3. Continuous Flow Solubility Continuous flow solubility of the tablets containing the MAV swellable polymer system was determined by placing the tablets in a thermostated beaker containing 150 µl of 37 ° C phosphate buffer, pH 5.5. . The test solution was passed continuously through a Sartorius membrane into a cuvette of a spectrophotometer (SP-9-100, Pye Unicam) using a peristaltic pump (Watson-Marlow, UK) and then pumped back into the beaker; the

MAP concentrations were also monitored by high performance liquid chromatography (HPLC). The dissolution rates determined under the above conditions are given in Table III. table.

The dissolution rates of the MAP-swellable pilimer systems are, according to the data in the table, much higher than those of a commercially available tablet or a mixture of the crystalline MAP and the crosslinked PVP which is the base material. The above results demonstrate the importance of coupling MAP to swelling poly10, which can be accomplished by any of the three methods.

III. Table 7: Dissolution Rate of MAP Swelling Polymer Systems under Continuous Flow in Phosphate Buffer pH 5.5

MAP preparation Dissolution rate (mg / min) Commercial tablet ³ (Contains 250 mg crystalline MAP) 0.144 physical mixture of starting crystalline MAP and starting crosslinked PVP 13 at ⁶ (3 h separated 0.041 grinding) Tablets containing 13 mixture of MAP crosslinked PVP system ⁰ (formulation according to Example 2), grinding 0.428 method (3 hours) Tablet ⁰ containing 15 ratio MAP-crosslinked PVP system (Example 6 formulation), heat treatment method 0,500 Tablets containing 15 mixture of MAP crosslinked PVP system ⁰ (formulation according to Example 8), duzzasztásos 0.530 method

Composition ^of 250 mg of crystalline MAP, 121.5 mg lactose 60.00 mg corn starch 22.50 mg of linear poly (vinyl pyrrolidone), 31.25 mg of sodium carboxymethyl starch, magnesium 5 mg stearate ^b contains 50 mg MAP

Bioavailability of MAP swelling polymer systems

The bioavailability of the MAP scavenging polymer systems produced by the process of the present invention was compared with that of a commercially available MAP formulation and with the physical mixture of the initial MAP and the initial crosslinked PVP.

The study was conducted by administering the above preparation orally (cross-over design) to six dogs (beagle, male and female, 9-13 kg), which were treated 17 hours before the start of the experiment and 4 hours after treatment. we stopped the food for an hour. At treatment intervals, 4 ml blood samples were collected, transferred to a heparinized tube and centrifuged at 3000 rpm for 10 minutes. The separated plasma was frozen at -20 ° until analysis.

Plasma levels of MAP were determined by a specific, highly accurate method as follows. The MAP was extracted with n-hexane, the extract was purified by partitioning with acetonitrile and subjected to high performance liquid chromatography (column: Lichrosorb RP 18 Merck, mobile phase: methanol / water 75:25, flow rate: 1 ml / min) : UV at 242 nm).

In the first study, the dogs were treated orally (cross-ver design) with a commercial formulation containing 250 mg MAP and crosslinked PVP loaded with 50 mg MAP prepared by grinding, heat treatment and swelling.

The test results are shown in Table IV. in Table. The results show that the plasma levels of MAP after treatment with the MAP-crosslinked PVP composition of the present invention are comparable to, or even higher than, those obtained with commercially available pentagonal higher MAP doses. The AUC values (7 hours) also confirm the increased bioavailability of MAP from commercially available MAP-crosslinked PVP systems.

194,050 products in the market.

In another study, dogs were treated orally (cross-over design) separately from a physical mixture of MAP 50 mg MAP and PVP13 for 3 hours, and tablets prepared from MAP crosslinked PVP 13 for 3 hours. The test results are shown in Table V. The results show that after treatment with the MAP-crosslinked PVP system produced by the method of the invention, plasma levels and AUC (7 hours) increased significantly compared to the values obtained with the physical mixture of MAP and crosslinked PVP.

The above results and the results of the above bt in vitro assays show that the MAP swellable polymer systems produced by the present invention improve the solubility properties of MAP and increase the bioavailability.

ARC. Table: Bioavailability of MAP Swellable Polymer Systems in Dogs (HPLC Methods, Mean Values, and Standrad Errors from 6 Dogs)

Time (Hours) commercial tablet ³ 1 x 250 mg MAP Plasma concentration of MAP (mg / ml) MAP Crosslinked PVP ^d 13 Ratio System Grinding Method 1 x 50 mg MAP MAP crosslinked PVP ^b 1: 5 system, heat treatment method 1 x 50 mg MAP MAP Crosslinked PVP ^C 1: 5 System Swelling Method 1 x 50 mg MAP 1 12.94 (2.80) 19.16 (6.35) 23.48 (5.50) 94.65 (39.56) 2 20.33 (7.49) 14.00 (2.52) 41.38 (13.62) 69.21 (19.93) 4 26.73 (18.48) 10.72 (1.95) 16.06 (4.87) 34.96 (35.45) 7 9.51 (2.94) 8.74 (3.74) 8.52 (2.51) 11.63 (2.73) AUC® (0-7 hours) (meg x hours / ml) 124.5 (48.1) the 80.07 (9.42) 138.50 (32.30) 303.31 (83.52)

^a : Composition: 250 mg crystalline MAP, 121.25 mg lactose, 60.00 mg corn starch, 22.50 mg linear polyvinylpyrrolidone, 31, 25 mg sodium carboxymethylcellulose starch, 5 mg magnesium stearate. Tablet Preparation Example 6 Tablet Preparation Example 8 ^a : Tablet Preparation Example 2 ^e : Area under the MAP Palma Concentration Time Curve

Table V: Bioavailability Study in Dogs (Determination of MAP Concentration by HPLC) (Averages and Standards)

Time (Hours) Plasma concentration of MAP (ng / ml) Control Tablet ⁸ (Ground MAP and ground crosslinked PVP 13 wt.% physical mixture based on 5 dogs) 2 x 50 mg MAP MAP-crosslinked PVP ^b 13 weight system, grinding average based on 6 dogs 2 x 50 mg MAP 4 9.71 (3.91) 86.67 (41.81) 2 13.24 U6.62) 95.99 (29.41) 4 31.19 (14.30) 79.58 (44.58) 7 11.01 (2.80) 25.41 (9.10) AUC® (0-7 hours) (meg x hours / ml) 123.57 (35.45) 467.7 (150.11)

^a : Composition: 200 mg of a 13% w / w physical mixture of MAP and crosslinked PVP separately for 3 hours, 40 mg of crosslinked PVP disintegrant; each dog is a tablet containing 50 mg MAP. has received 2 times. the tablets were prepared as in Example 2; each dog received twice daily tablet containing 50 mg MAP ^c : area under the MAP plasma concentration-time curve

Claims (3)

A process for incorporating 1 part by weight of methyl hydroxy progesterone acetate (MAP) into 0.1 to 100 parts by weight of a water-swellable, insoluble polymer, characterized in that: a) grinding the mixture of polymer and MAP; obsession b) preparing a mixture of polymer stable at the melting point of MAP and MAP and heating it to a temperature corresponding to the melting point of MAP; obsession c) swelling the polymer with a MAP solution in a solvent capable of swelling the polymer and drying the lost swollen MAP polymer system. . The process of claim 1 wherein two or more water swellable polymers are used. 3. The process according to any one of claims 1 to 3, wherein the swellable, water-insoluble polymer is crosslinked polyvinylpyrrolidone. 4. The process according to any one of claims 1 to 3, wherein the swellable, water-insoluble polymer is sodium carboxymethylcellulose.